title: TDP-43 regulates the microprocessor complex activity during in vitro neuronal differentiation.
abstract: TDP-43 (TAR DNA-binding protein 43) is an RNA-binding protein implicated in RNA metabolism at several levels. Even if ubiquitously expressed, it is considered as a neuronal activity-responsive factor and a major signature for neurological pathologies, making the comprehension of its activity in the nervous system a very challenging issue. TDP-43 has also been described as an accessory component of the Drosha-DGCR8 (DiGeorge syndrome critical region gene 8) microprocessor complex, which is crucially involved in basal and tissue-specific RNA processing events. In the present study, we exploited in vitro neuronal differentiation systems to investigate the TDP-43 demand for the microprocessor function, focusing on both its canonical microRNA biosynthetic activity and its alternative role as a post-transcriptional regulator of gene expression. Our findings reveal a novel role for TDP-43 as an essential factor that controls the stability of Drosha protein during neuronal differentiation, thus globally affecting the production of microRNAs. We also demonstrate that TDP-43 is required for the Drosha-mediated regulation of Neurogenin 2, a master gene orchestrating neurogenesis, whereas post-transcriptional control of Dgcr8, another Drosha target, resulted to be TDP-43-independent. These results implicate a previously uncovered contribution of TDP-43 in regulating the abundance and the substrate specificity of the microprocessor complex and provide new insights into TDP-43 as a key player in neuronal differentiation.
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, P.le A. Moro 5, 00185, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.forename: Elena
authors.initials: E
authors.lastname: Grossi
authors.forename: Pietro
authors.initials: P
authors.lastname: Laneve
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morlando
authors.forename: Stefano
authors.initials: S
authors.lastname: Dini Modigliani
authors.forename: Monica
authors.initials: M
authors.lastname: Ballarino
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Caffarelli
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000166:cytology*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D061988:Proteasome Inhibitors; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; C474043:DGCR8 protein, human; C491183:NEUROG2 protein, human; C517918:DROSHA protein, human